Phenoxazine derivatives

Allylic diacetates were converted into N,N, 0,0, and N, O-heterocycles in a palladium catalyzed two step nucleophilic displacement sequence. The reaction of o-aminophenol and cyclopentenyl-diacetate, for example, gave the cyclopentene condensed phenoxazine derivative in acceptable yield (4.21.), while o-phenylenediamine and catechol gave the corresponding phenazine and dioxine derivative in good yield.24... 

Table 4 Changes in polyamine levels during cell death induced by 3 hours of phenoxazine derivatives (WM7, WM8)...

This article is a summary of our recent extensive study of tumor specificity (TS) and the type of cell death induced by N-containing heterocycles such as 4-trifluoromethylimidazole [22] and phenoxazine derivatives [23], by O-containing heterocycles such as 3-formylchromone [24] and coumarin derivatives [25,26], and by other compounds such as vitamin K2 and prenyl-alcohols [27]. 

Actinomycin D has been clinically used for the treatment of many cancers and is known to be a DNA intercalator. The structure of actinomycin D is based on a phenoxazine ring bound to two cyclic pentapeptides [33]. The presence of the phenoxazine ring in the structure of actinomycin D suggests that phenoxazine derivatives may possess anticancer activity. Phenoxazine derivatives are known to be effective multidrug resistance (MDR) modulators in cancer cells [34], potent inhibitors of Akt signaling in cells [35], inhibitors of human plasma cholinesterase [36], and photo-chemotherapeutic agents in cancer cells [37]. Recent studies also show that the relatively water-soluble phenox-azines, such as 2-amino-4,4a-dihydro-4a,7-dimethyl-2H-phenoxazine-3-one and 2-aminophenoxazine-3-one, exert antitumor effects on various cancer cells in vitro and in vivo. [38]. We have investigated 24 phenoxazines [23,39] (Fig. 4). 

Polarographic,35 chromatographic, and electrophoretic 36 investigations on phenoxazine derivatives have been reported for naturally occurring phenoxazones (actinomycins). 

Recent investigations have shown the existence of a number of phenoxazine derivatives in nature, which, with a few exceptions only,... 

Besides potential pharmacological applications, a number of other uses have been described for phenoxazine derivatives. The semi-quinone radical obtained on oxidation of phenoxazine with various oxidants, which has been shown to give a characteristic absorption at about 530 mp., was used by Sawicki et al.110 in a new method for the spectrophotometric determination of nitrite the aqueous nitrite sample is treated with a 0.1% solution of phenoxazine in glacial acetic acid and the absorbance is read at 530 mp. 

Mention should be made of oxazine dyes, used also as biological stains, which are oxidized phenoxazine derivatives containing suitable auxochromic groups. A detailed treatment of these dyes, however, is beyond the scope of this review. Most of the industrial phenoxazine dyes are derived from benzophenoxazines (e.g., Meldola s blue) or from more complex ring systems containing the phenoxazine residue (triphendioxazine dyes).3,118 The long-known dyestuffs orcein and litmus which are prepared by the action of ammonia on certain lichens, and may also occur accidentally in nature, are both based on the oxidized phenoxazine ring system as shown by Musso and co-workers.119... 

Kelly reported the preparation of several transthyretin amyloid fibril inhibitors using the BINAP/Pd-catalyzed coupling [120]. For example, the coupling below furnished the desired phenoxazine derivative in 70% isolated yield, Eq. (146). 

Fig. 5 Structures of phenoxazine derivatives used in this study...

We have recently found that among 24 phenoxazine derivatives, 7 and 8 showed the highest tumor-specificity indexes of 4.3 and 4.8, respectively [37]. 7 and 8 did not apparently induce intranucleosomal DNA fragmentation, nor activate caspase-3 in HSC-2, HSC-4, and human glioblastoma T98G cells. We investigated the QSAR of 15 phenoxazine derivatives (Fig. 5) [38], using conventional and recent techniques of computation chemistry, such as the concept of chemical hardness [16-18]. 

By determining the most stable conformation of 15 phenoxazine derivatives, their structure was approximated to the molecular form present in vivo (biomimetic). The most stable structure was next determined by CAChe Worksystem 4.9 MOPAC (PM3) (Fig. 6). The CC50 value (determined by experiments) of phenoxazines against HSC-2, HSC-3, HSC-4, and HL-60 cells, and chemical descriptors (determined by calculations) heat of formation... 

Fig. 6 The most stable conformation of each phenoxazine derivative used...

Fig. 7 Relationship between CC50 and each chemical descriptor of phenoxazine derivatives against HSC-2 (a-k), HSC-3 (I), and HL-60 cells (m, n)...

Fig. 8 r] x activity diagram between the electron structure and the cytotoxicity of phenoxazine derivatives. The box surrounds compounds with higher cytotoxicity (lower CC50)... 

Various redox compounds that fulfil catalyst characteristics have been investigated in systems with recycling of NAD by electrocatalytic methods. Quinones, formed either by oxidation of carbon surfaces [143, 145] or adsorbed to the electrode surface [146, 147], phenazines [148, 149], phenoxazine derivatives such as Meldola Blue [182], 9-naphthoyl-Nile Blue [151, 152] and l,2-benzophenoxazine-7-one [153], and also the organic conducting salt N-methyl phenazinium tetracyanoquinodimethanide (TTF TCNQ") [154, 155], ferricinium ions [156, 157] and hexacyanoferrat(IIl) ions [158, 159] can act as catalysts for the electrochemical oxidation of NADH. It is assumed that in corresponding electron-transfer reactions a charge-transfer complex between the immobilized mediator and NADH is formed. The intermediate reduced redox mediator will be reoxidized electrochemically. Most systems mentioned, however, suffer from poor electrode stabilities. 

Kolchina, E.F. Gerasimova, T.N. Cyclization of polyfluorinated 2-amino- and 2-acetamidodiaryl ethers into phenoxazine derivatives. Izv. Akad. Nauk SSSR 1990, 4, 846-849. 

Most adsorbed phenoxazine derivatives give slightly broader peaks than what is theoretically stipulated for a Langmuirian adsorption process. The number n, whether evaluated from the o.5 or from eqn.(l), is usually somewhat lower than two, reflecting interactions between the adsorbed molecules. The immobilization process may strongly influence the properties of the adsorbed species, which is clearly revealed for Nile Blue in Fig.3. Both the energy level, as well as the various pKa-values of the oxidized and the reduced forms, are changed on adsorption. " ... 

ScHLUNEGGER, U.P., A. KucHEN, and H. Clemen on Mycelprodukte Hoherer Pilze 1. Phenoxazin-Derivate in Calocybe gambosa. Helv. Chim. Acta 59, 1383 (1976). 

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